Proliferative diseases such as vascular restenosis, scleroderma, psoriasis, and rheumatoid arthritis share the fundamental mechanism of excessive proliferation of cells in a specific tissue or organ. In each of these diseases, the excessive proliferation of cells contributes significantly to the pathogenesis of the disease.
For example, the excessive proliferation of vascular smooth muscle cells contributes to the reocclusion of coronary arteries following percutaneous transluminal coronary angioplasty (PTCA), atherectomy, laser angioplasty and arterial bypass graft surgery. See "Intimal Proliferation of Smooth Muscle Cells as an Explanation for Recurrent Coronary Artery Stenosis after Percutaneous Transluminal Coronary Angioplasty," Austin et al, Journal of the American College of Cardiology 8:369-375 (Aug. 1985).
Vascular restenosis remains a major long term complication following surgical intervention of blocked arteries by percutaneous transluminal coronary angioplasty (PTCA), atherectomy, laser angioplasty and arterial bypass graft surgery. In about 35% of the patients who undergo PTCA, reocclusion occurs within three to six months after the procedure. The current strategies for treating vascular restenosis include mechanical intervention by devices such as stents or pharmacologic therapies including heparin, low molecular weight heparin, coumarin, aspirin, fish oil, calcium antagonist, steroids, and prostacyclin. These strategies have failed to curb the reocclusion rate and have been ineffective for the treatment and prevention of vascular restenosis. See "Prevention of Restenosis after Percutaneous Transluminal Coronary Angioplasty: The Search for a `Magic Bullet`, " Hermans et al., American Heart Journal 122:171-187 (July 1991).
The excessive proliferation of fibroblast and mesenchymal cells is associated with rheumatoid arthritis and psoriasis. The inflammatory process that is characteristic of rheumatoid arthritis results in the release of growth factors that induce active proliferation of mesenchymal cells. This proliferation is associated with the production of excessive amounts of enzymes capable of destroying the connective tissues that comprise the joint. Pharmacologic agents that inhibit the proliferative response would be effective in repressing some of the destructive potential of rheumatoid arthritis. See "Recent Insights into the Pathogenesis of the Proliferative Lesion of Rheumatoid Arthritis," Harris, Arthritis and Rheumatism 19:68-72 (January-February 1976).
Scleroderma (systemic sclerosis) is a multisystem disease affecting primarily the vascular, cutaneous, musculoskeletal, gastrointestinal, pulmonary, cardiac, and renal systems. The apparent diffuse clinical features of systemic sclerosis are thought to be linked by a distinctive vascular lesion in the various target organs. This vascular lesion has inflammatory, proliferative, and indurative phases and is clearly related to the proliferation of the fibroblast and cells capable of fibroblast activity. Controlling this mechanism of fibroblastic activation and proliferation may be useful in treating or preventing systemic sclerosis. See "Pathogenesis of Systemic Sclerosis: A Vascular Hypothesis," Campbell et al., Seminars in Arthritis and Rheumatism 4:351-368 (May, 1975).
In the pathogenesis of proliferative diseases, excessive cell proliferation occurs as a result of the presence of various growth factors and cytokines such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), fibroblast growth factor (FGF) and interleukin-1 (IL-1). For example, growth factors produced by cellular constituents in the blood and the damaged arterial vessel wall mediate the proliferation of smooth muscle cells in vascular restenosis. A novel method of administering dipyridamole to inhibit cellular proliferation caused by various growth factors is therefore useful for the treatment of proliferative diseases such as psoriasis, rheumatoid arthritis, scleroderma, and vascular restenosis. The American Journal of Medicine 70:1231-1236 (June 1981).
Dipyridamole is commonly prescribed as an antiplatelet or phosphodiesterase inhibitor. It has been studied independently or in conjunction with aspirin and/or prostacyclin for the treatment of vascular restenosis. The results of these studies have demonstrated that dipyridamole, when systemically administered, is ineffective in treating or preventing vascular restenosis in patients. Hermans et al., American Heart Journal 122: 171-187 (July 1991); Harker et al., Arteriosclerosis 10: 828a (September-October, 1990); and FitzGerald, The New England Journal of Medicine 316:1247-57 (May, 1987).
The present invention provides for the use of dipyridamole as an antiproliferative agent. The invention discloses the local delivery of dipyridamole as a method of inhibiting cell proliferation and is useful for the treatment of proliferative diseases such as restenosis, scleroderma, psoriasis, and rheumatoid arthritis.